Abstract

Vertebrate animals exhibit four mechanisms of tissue regeneration: re‐growth of cellular parts, such as nerve axons; lineage‐specific
proliferation of differentiated cells with or without dedifferentiation; transdifferentiation and activation of adult stem
cells. The most common mechanism is the proliferation and differentiation of adult stem cells, used by epithelia, muscle,
bone and blood. In some cases, such as the liver and pancreas, regeneration is accomplished by either lineage‐specific proliferation
of differentiated cells or a stem cell population, depending on the nature of the damage. All four mechanisms are used by
urodele salamanders in the regeneration of limbs. The cellular activities in all these mechanisms are regulated by a wide
variety of growth factor signalling pathways and transcription factors. Regenerative medicine uses three major strategies
based on knowledge of regenerative mechanisms: transplants of stem cells or their derivatives, construction of bioartificial
tissues composed of natural or synthetic biomaterials seeded with cells and the pharmaceutical induction of regeneration at
the site of injury by natural or synthetic regeneration‐promoting molecules.

Key Concepts

Regeneration restores the original structure and function of damaged or missing tissues.

Tissues use four mechanisms to regenerate: re‐growth of cell parts, lineage‐specific reproduction of parent cells, transdifferentiation
and activation of adult stem cells.

Some tissues use more than one mechanism of regeneration.

Growth factor signals and transcription factors are important regulators of regeneration.

Regenerative medicine uses three strategies to regenerate damaged tissues: cell transplants, bioartificial tissue implants
and pharmaceutical induction of regeneration directly at the site of damage by scaffolds or soluble molecules.

The source of cells for transplants and bioartificial tissues is a crucial issue for regenerative medicine.

Induced pluripotent stem cells (iPSCs) and/or transdifferentiation may solve many of the problems presented by adult and embryonic
stem cells.

Figure 1. The four mechanisms of regeneration. (a) Cellular re‐growth. MN = motor neuron; AX = axon; M = muscle. The vertical green
line indicates the level of transection and the arrow indicates regeneration of the axon to its target muscle. (b) Lineage‐specific
regeneration from differentiated parent cells by compensatory hyperplasia (CH) or dedifferentiation/redifferentiation (D/R).
Compensatory hyperplasia is the proliferation of cells while maintaining their differentiated structure and function. Dedifferentiation/redifferentiation
involves dedifferentiation (D) of the cell to a progenitor state, followed by proliferation (P) and redifferentiation (R)
into the parent cell type. (c) Transdifferentiation is the conversion of one cell type to another. Direct transdifferentiation
(T, upper arrow) involves a switch in gene activity without going through an intermediate state. Indirect transdifferentiation
(lower part of diagram) involves dedifferentiation (D) of the cell to a plastic intermediate state, followed by transdifferentiation
(T). (d) Adult stem cell activation. Adult stem cells (ASCs) divide asymmetrically to self‐renew (SR) and produce a lineage‐committed
progenitor (LC). The progenitor proliferates (P) and then differentiates (D).

Figure 2. Transdifferentiation of pigmented dorsal iris cells into lens cells after lentectomy in the newt. Tissue factor is selectively
produced by non‐endothelial cells by injured vessels of the dorsal iris, leading to thrombin activation and clot formation
(red). Macrophages attracted to the clot release PDGF and TGF‐β3 that induce the dorsal pigmented iris cells to produce FGF‐2
and its receptor at higher levels dorsally (+3 vs +1), which in turn leads to a higher level of Wnt signalling through its
receptor. The result is the dedifferentiation and proliferation of these cells to form a lens vesicle (green circle).

Figure 3. Strategies of regenerative medicine. (a) Cell transplantation. The example is bone marrow cells (yellow) injected into a region
of myocardial infarct of the heart. (b) Bioartificial tissue construction. A matrix (blue) is seeded with cells (yellow).
(c) Pharmaceutical induction of regeneration. Growth factors or transcription factors, or their genes (black dots), are injected
into a damaged organ such as the heart. The growth factors act as anti‐scarring and cell survival agents. Transcription factors
could be used to transdifferentiate cardiac fibroblasts to cardiomyocytes.